Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease
Unlocking Cerebral Small Vessel Disease: A Proteogenomic Breakthrough
Our groundbreaking analysis of over 2,500 proteins in cerebrospinal fluid (CSF) and plasma unveils a robust biological fingerprint for cerebral small vessel disease (cSVD). This discovery opens new avenues for biomarker development and drug repositioning, addressing a critical need in stroke and dementia prevention.
Quantifiable Impact: Key Findings at a Glance
Our rigorous methodology across diverse datasets yields actionable insights.
49
cSVD-Associated Proteins Identified
5x
CSF Associations vs. Plasma (times more)
7
Existing Drug Targets Identified
Deep Analysis & Enterprise Applications
Select a topic to dive deeper, then explore the specific findings from the research, rebuilt as interactive, enterprise-focused modules.
Utilizing Mendelian Randomization (2SMR) on an unprecedented scale, we analyzed over 2,500 proteins in both plasma and cerebrospinal fluid (CSF) against MRI markers of cSVD across more than 40,000 individuals. This systematic approach allowed us to identify causal links between protein levels and cSVD pathology, highlighting the unique value of CSF in revealing disease mechanisms.
To ensure the robustness and generalizability of our findings, we conducted extensive follow-up analyses. These included cross-fluid comparisons, validations across different proteomic platforms (SomaScan vs. Olink), diverse ancestries (European, East Asian), and different life stages (young adults, older adults), using both 2SMR and complementary observational methods.
Our identified proteins are predominantly enriched in pathways related to the extracellular matrix, immune response, and microglial activity, suggesting key biological processes underlying cSVD. Single-cell sequencing resources were leveraged to pinpoint specific cell types involved, offering deeper mechanistic insights into cSVD progression.
Beyond biological insights, we assessed the clinical implications, finding significant associations between cSVD-linked proteins and the risk of stroke and dementia. Crucially, several of these proteins correspond to existing drug targets, paving the way for drug repositioning strategies that could accelerate therapeutic development for cSVD.
49
Proteins Robustly Associated with cSVD Markers
Our Proteogenomic Discovery Pipeline
Protein pQTLs (CSF/Plasma)
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2SMR (MRI-cSVD GWAS)
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Causal Proteins Identified
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Follow-up Validation
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Pathway/Cell Type Analysis
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Drug Target Discovery
| Feature | Cerebrospinal Fluid (CSF) | Plasma |
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Case Study: PILRA - A Microglial Immunoreceptor
Challenge: Cerebral amyloid angiopathy (CAA) subtype of cSVD and Alzheimer's disease (AD) share underlying pathologies involving Aβ uptake and immune response.
Solution: Our 2SMR analysis consistently linked higher CSF and plasma PILRA-M14/deltaTM levels with smaller WM-PVS burden, suggesting a protective role. This aligns with previous work on PILRA as a causal gene in AD risk, regulating Aβ uptake and herpes simplex virus 1 infection in microglia.
Result: PILRA isoforms (microglial immunoreceptor) were identified as robustly associated with cSVD, consistent across platforms and ancestries, and showed lifespan effects. This highlights PILRA as a key biological fingerprint and potential therapeutic target for cSVD and AD.
Case Study: EPO - Repositioning for Neuroprotection
Challenge: Lack of specific treatments for cSVD, necessitating the discovery of new therapeutic targets or repurposing existing drugs.
Solution: Our analysis identified a protective effect of higher genetically determined CSF EPO levels on WMH volume. EPO is a known neuroprotective protein, and its analogs are already in Phase II clinical trials for depression and neuropathy. While plasma EPO showed a deleterious effect (likely reflecting distinct sources), CSF EPO's protective role is compelling.
Result: EPO is highlighted as a promising candidate for drug repositioning for cSVD. Its ability to cross the BBB and existing clinical trial data make EPO analogs a strong candidate for further investigation into cSVD neuroprotection.
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Implementing AI for Biomarker Discovery: Our Proven Roadmap
Our systematic process ensures rapid, reliable, and actionable insights for your enterprise.
Phase 1: Data Integration & Harmonization
Seamlessly integrate diverse proteogenomic datasets (CSF, plasma, GWAS, MRI) from global cohorts, ensuring data quality and cross-platform compatibility.
Phase 2: Advanced Causal Inference (2SMR)
Apply cutting-edge Mendelian Randomization techniques to identify robust causal links between protein levels and disease markers, minimizing confounding.
Phase 3: Multi-Layered Validation
Validate findings across various dimensions – different biological fluids, proteomic technologies, ancestries, and developmental stages – to confirm reliability and generalizability.
Phase 4: Biological Pathway & Cell-Type Deconvolution
Pinpoint the specific biological pathways (e.g., ECM, immune response) and cell types (e.g., microglia) implicated in disease, leveraging single-cell sequencing resources.
Phase 5: Therapeutic Target & Repositioning Strategy
Translate discoveries into actionable therapeutic strategies, identifying novel biomarkers and prioritizing existing drug targets for rapid repositioning, accelerating clinical translation.
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